Hypertension Clinical Trials Research Articles

Effects of amlodipine on cardiovascular outcomes in hypertension clinical trials: traditional and network meta-analyses

CI 1⁄4 confidence interval; CV 1⁄4 cardiovascular; CHD 1⁄4 coronary heart disease; MACE 1⁄4 major adverse CV events (stroke, CHD, CV death; estimated for some trials); HF 1⁄4 heart failure. These data suggest that, in clinical trials, amlodipine significantly increased the risk of heart failure, but prevented other cardiovascular endpoints at least as well as other regimens, including those that started with a diuretic.

The need to move from 6-minute walk distance to outcome trials in pulmonary arterial hypertension

Assessment of change in exercise capacity using the 6-min walk distance (6MWD) test has been the primary end-point in the majority of pulmonary arterial hypertension (PAH) clinical trials. The 6MWD has some advantages as an end-point in such studies. It is simple and inexpensive to perform, reproducible and validated. In short-term studies with small patient numbers, as is typical in a rare disease like PAH, using change from baseline in 6MWD as the primary outcome measure demonstrated statistically significant differences between placebo and study drugs, leading to their approval. However, there have been increasing calls for clinical trials to employ primary end-points that reflect long-term disease progression and morbidity. While the 6MWD was initially considered to be a potentially reliable surrogate for disease progression in PAH, there is increasing evidence that this is not necessarily the case. Given this, there is a need to re-examine the role of 6MWD in PAH trials, and to evaluate the evidence supporting whether there is a need to move from 6MWD to more robust measures of clinical outcomes, such as morbidity and mortality. However, in the clinic the 6MWD test, alongside symptoms, haemodynamics and biomarkers, remains a useful tool in the assessment and management of PAH patients.

Updating Clinical Endpoints in Pulmonary Arterial Hypertension: When Challenges are Welcome

We thank Ms. Deborah McCollister for her feedback on our recent article titled “Updating clinical endpoint definitions.” McCollister judiciously points out some of the challenges raised with the recent trend among investigators and pharmaceutical companies involved in pulmonary arterial hypertension (PAH) clinical trials to move away from the 6‐minute walk distance (6MWD) as a primary outcome in favor of a more composite endpoint, such as time to clinical worsening (TTCW), which includes elements of morbidity (such as hospitalization, clinical worsening, and need for additional therapy) and mortality.

Motivation and frustration in cardiology trial participation: The patient perspective

OBJECTIVE:The participation of humans in clinical cardiology trials remains essential, but little is known regarding participant perceptions of such studies. We examined the factors that motivated participation in such studies, as well as those that led to participant frustration.METHODS:Patients who had participated in hypertension and coronary arterial disease (phases II, III, and IV) clinical trials were invited to answer a questionnaire. They were divided into two groups: Group I, which included participants in placebo-controlled clinical trials after randomization, and Group II, which included participants in clinical trials in which the tested treatment was compared to another drug after randomization and in which a placebo was used in the washout period.RESULTS:Eighty patients (47 patients in Group I and 33 patients in Group II) with different socio-demographic characteristics were interviewed. Approximately 60% of the patients were motivated to participate in the trial with the expectation of personal benefit. Nine participants (11.2%) expressed the desire to withdraw, which was due to their perception of risk during the testing in the clinical trial (Group I) and to the necessity of repeated returns to the institution (Group II). However, the patients did not withdraw due to fear of termination of hospital treatment.CONCLUSIONS:Although this study had a small patient sample, the possibility of receiving a benefit from the new tested treatment was consistently reported as a motivation to participate in the trials.

The Reporting of Harms in Randomized Controlled Trials of Hypertension Using the CONSORT Criteria for Harm Reporting

The aim of this study was to assess the quality of reporting of harms in hypertension clinical trials identified from the Cochrane Database using the Consolidated Standards of Reporting Trials (CONSORT) extension for harms reporting. Forty-one hypertension trials were included in the study. On average trials reported less than half of the items recommended by the CONSORT extension for harms (mean 9.83 items; 95% confidence interval = 8.06, 11.60). Trialists need to address the perceived shortcomings in measurement, analysis, and reporting of harms data so that the available trial data can be considered as a balanced and reliable source of evidence.

Abstract P249: Patient Centered Care: Baseline Demographics Data From a Stage I Hypertension Clinical Trial

Background: Hypertension is highly prevalent in underserved communities and is associated with excess cardiovascular mortality. Patient Centered Care (PCC) programs are essential to achieve adequate blood pressure control and modify CVD risk. Use of the Internet to report self measured BP is one method to achieve better BP control. However, in underserved populations, Internet access is limited. We tested whether low income and lack of home Internet access limits BP management with a telemedicine program. Methods: Inner-city, primarily African-American (AAs) patients (N=130) with uncontrolled HTN (BP>140/90 mmHg) who are followed by primary care physicians were randomized to usual care or Telemedicine plus usual care. BP, weight, BMI, blood glucose, lipids, tobacco use, and physical activity were measured at baseline and at 6 months. Income level and availability of Internet were recorded for each patient. We divided the income level in five groups: 1) $15,000-$24,999, 2) $25,000-34,999, 3) $35,000-44,999, 4) $45,000-54,999, and 5) >$55,000. We correlated each group with Internet availability at home, age, sex, race, blood pressure, smoking, and hyperlipidemia. Results: Baseline demographics include age 58±17 years, BMI 33±8 kg/m 2 , SBP: 152±13 mmHg, DBP: 86±11 mmHg, FBS: 112±46 mg/dL, HbA1C: 6.3±1.6%, total cholesterol: 178±47, HDL: 50±16, LDL: 99±47. Sixty eight %were African American, 19% were smokers, 32% diabetics, and 42% had hyperlipedemia. Home internet was available to 46%. 52% fell under the low income groups (1+2). When compared between the income groups, group 1 and 2 showed significant differences (p=0.004 and p=0.013) with group 5 (p=0.002) in terms of availability of Internet at home. Patients with no internet access used inter-active computerized telephone system for communication with our center. Conclusions: Many inner city patients could not utilize Internet based telemedicine to take a more active role in their own health care through self-monitoring, education, reinforcement and feedback. They were able to use telephone based communication to benefit from patient centered care.

Implications of Ambulatory Blood Pressure Monitoring Substudies on the Interpretation of Clinical Trials in Hypertension: Should the Threshold for Drug Therapy Be Lower in Older Patients?

Implications of Ambulatory Blood Pressure Monitoring Substudies on the Interpretation of Clinical Trials in Hypertension: Should the Threshold for Drug Therapy Be Lower in Older Patients?

Néphroangiosclérose

Hypertensive nephrosclerosis is the leading cause of end stage renal disease (ESRD) in France, however, in prospective clinical trials of hypertension, ESRD accounts only for a small fraction of all events (incidence rate 0.2 to 0.4% by year). Hypertensive nephrosclerosis is characterized histologically by a series of vascular injury, none of which is truly specific and that can be observed also in obesity or normal aging. Hypertensive nephrosclerosis is mildly symptomatic, but the prognosis is never benign, due to cardiovascular and renal burden. This unspecific presentation may explain why the diagnosis of hypertensive nephrosclerosis is easily carried by excess, the main differential diagnoses are atherosclerotic ischemic renal disease, poorly symptomatic primitive nephropathies or the sequelae of unnoticed malignant hypertensive nephrosclerosis. The very high prevalence of hypertensive nephrosclerosis in populations from African ancestry has suggested a genetic predisposition. MYH9/APOL1 gene variants have recently been identified and are strongly associated with hypertensive nephrosclerosis, however the pathophysiological link between these variants and renal disease is still unclear. The treatment is mainly based on blocking the renin angiotensin system, especially when proteinuria is present. The target blood pressure is less firmly established, the latest data from the AASK study, however, do suggest a benefit on progression of lower values < 135/80 or even < 130/80 mmHg, especially in patients with proteinuria.

To ACCELERATE Hypertension Control

Introduction: According to the latest report from the US Centers for Disease Control and Prevention [1], 31% of adult population of the United States was reported to have hypertension between 2005 and 2008. Of this population, 70% received antihypertensive therapy, and of these, 46% had their condition controlled. Although these results show some improvements compared to previous reports [2], hypertension control is still less than optimal. This public health problem is associated with a major economic burden. Hypertension contributes to increased cardiovascular morbidity and mortality that costs nearly $300 billion a year. Thus, developing strategies to improve hypertension control constitutes a major goal. Most of the major hypertension clinical trials have suggested that a minimum of two antihypertensive drugs are needed to get blood pressure (BP) under control [3–5], but despite the availability of this information, the use of multiple drug therapy in managing hypertension is not widely practiced.

The Clinical Application of Ambulatory Blood Pressure Monitoring in Pediatrics

Management of hypertension (HTN) largely relies on proper and accurate measurement of blood pressure (BP). Even following the criteria for HTN diagnosis defined in the Fourth report on high BP in children and adolescents, inaccurate diagnosis and misdiagnosis can occur with white coat effect and masked HTN. The use of Ambulatory Blood Pressure Monitoring (ABPM) has been increasing in pediatrics in the last 20 years. The main use of ABPM is to differentiate between sustained HTN and white coat HTN in patients who have elevated casual BP measurements and to detect masked HTN in high risk patients. ABPM is most useful in patients with casual BP within 20% of the 95th percentile for age, gender, and height. This report will highlight the use of ABPM in the evaluation of elevated BP and management of HTN in pediatrics. The discussion includes a review of various non-invasive BP measuring techniques, a description of ABPM and ABPM-unique data and diagnoses, updated ABPM clinical data more specific to pediatrics, its use in HTN clinical trials, and future outlook and direction of ABPM in pediatrics.

Treating the Black Hypertensive in 2010: Achieve Lower Targets While Awaiting More Definitive Evidence

Treating the Black Hypertensive in 2010: Achieve Lower Targets While Awaiting More Definitive Evidence

The Potential for Therapeutic Misconception in Pulmonary Arterial Hypertension Clinical Trials: A Case-Based Discussion

This case study illustrates several of the potential challenges frequently encountered by clinical investigators working in the area of pulmonary arterial hypertension (PAH). It raises the issues of therapeutic misconception and clinical equipoise, and illustrates the importance of informing potential research participants of all their options in explicit detail.20 It also emphasizes the importance of explaining to patients that they are being asked to participate in a study to advance medical knowledge and develop therapies for the population of patients with PAH, and not for their own benefit. While they may benefit from the study drug, if they in fact receive it, this should not be offered as a reason for their potential participation. In addition, investigators should disclose any potential conflicts of interest to potential participants. During the past 2 decades, such clinical trials have advanced the treatment of patients with PAH and continue to offer the possibility of further improvements in our treatment of this devastating disease.

Chronic Pain Is An Independent Predictor of Lower 6 Minute Walk Distance In Patients with Sickle Cell Disease: Results From Walk-PHaSST Study

AbstractAbstract 2658 Introduction:Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods:walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results:For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in < 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD >500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking > 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions:TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH.Table 1Odds Ratio estimates: Multivariable AnalysisParameterEstimateStandard ErrorWald 95% Confidence Limitsp-valueChronic Pain−27.28.0−42.9−11.60.0007TR Jet Velocity−30.69.9−49.9−11.10.0020Age−0.90.3−1.5−0.30.0022Sex−39.17.6−53.9−24.3<.0001 [Display omitted] Disclosures:Barst:Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

DAYTIME SYSTOLIC BLOOD PRESSURE LOAD AND PREVIOUS STROKE PREDICT CARDIOVASCULAR EVENTS IN TREATED OCTOGENARIANS WITH HYPERTENSION

DAYTIME SYSTOLIC BLOOD PRESSURE LOAD AND PREVIOUS STROKE PREDICT CARDIOVASCULAR EVENTS IN TREATED OCTOGENARIANS WITH HYPERTENSION

Are coronary revascularization and myocardial infarction a homogeneous combined endpoint in hypertension trials? The Losartan Intervention For Endpoint reduction in hypertension study

Construction of prognostically relevant endpoints for clinical trials in hypertension has increasingly included coronary revascularization with myocardial infarction (MI) as manifestations of coronary artery disease. However, whether coronary revascularization and MI predict other cardiovascular events similarly is unknown. We examined risks of cardiovascular death, all-cause death, and stroke following MI or coronary revascularization in hypertensive patients with left ventricular hypertrophy (LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). We studied 9113 patients after excluding those who died within 7 days after MI or underwent coronary revascularization within 24 h after MI. In multivariate Cox regression adjusting for participating countries, time-varying systolic blood pressure, and Framingham risk score, hazard ratios for cardiovascular death, all-cause death, and stroke were, respectively, 4.5 (P<0.0001), 2.9 (P<0.0001), and 1.9 (P=0.003) in 321 patients with MI as first event. In similar models, coronary revascularization as first event (n=202) was not associated with increased risks of cardiovascular death, all-cause death, and stroke (P=0.06-0.86). During follow-up of hypertensive patients with LVH, occurrence of MI but not coronary revascularization as first cardiovascular event significantly increased risk of subsequent cardiovascular death, all-cause death, and stroke. In view of differences in prognostic implications, when the goal is to have a prognostically relevant composite endpoint for trials in hypertensive patients, caution should be used in combining coronary revascularization with MI.

The Clock Is Ticking: The Case for Achieving More Rapid Control of Hypertension

The Clock Is Ticking: The Case for Achieving More Rapid Control of Hypertension

The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease

Macronutrient and micronutrient deficiencies are very common in the general population and may be even more common in patients with hypertension and cardiovascular disease due to genetic, environmental causes and prescription drug use. The Hypertension Institute in Nashville, TN, has evaluated micronutrient deficiencies and oxidation status, in a group of hypertensive versus normotensive patients. There are significant differences in numerous intracellular micronutrients and oxidation status between these two groups. Replacement of the micronutrient deficiencies, as well as high-dose therapy of selected nutraceuticals in combination with optimal diet, exercise and weight management resulted in control of blood pressure to goal levels in 62% of the hypertensive population (as defined by JNC 7) over a period of 6 months with complete tapering and discontinuation of antihypertensive drugs. These deficiencies will have an enormous impact on present and future cardiovascular health and outcomes such as hypertension, myocardial infarction, stroke and renal disease and overall health costs. It is estimated that the annual savings in drug costs alone for the treatment of hypertension could be as much as US$10 billion. Diagnosis and treatment of these nutrient deficiencies and improvement in oxidation status using functional intracellular assessments will reduce blood pressure, improve vascular health, endothelial dysfunction, vascular biology and cardiovascular events. Vascular biology assumes a pivotal role in the initiation and perpetuation of hypertension and target organ damage sequelae. Endothelial activation, oxidative stress, inflammation and vascular smooth muscle dysfunction are initial events that start hypertension. Nutrient-gene interactions determine a broad array of phenotypic consequences such as vascular problems and hypertension. Optimal nutrition, nutraceuticals, vitamins, antioxidants, minerals, weight loss, exercise, smoking cessation and moderate restriction of alcohol and caffeine in addition to other lifestyle modifications can prevent and control hypertension in many patients. An integrative approach combining these lifestyle suggestions with the correct pharmacologic treatment will best achieve new goal blood pressure levels, reduce cardiovascular risk factors, improve vascular biology and vascular health, reduce cardiovascular target organ damage and reduce healthcare expenditure. The expanded scientific roles for nutraceutical supplements are discussed in relation to the prevention and treatment of essential hypertension and cardiovascular diseases with emphasis on mechanisms of action and clinical integration with drug therapy with hypertension guidelines. It is the purpose of this paper to review only the hypertension clinical trials that have evaluated the clinical use and efficacy of nutrition, weight loss, exercise and selected nutritional supplements, vitamins, minerals and antioxidants. Numerous clinical trials have evaluated the use of nutritional supplements such as beta carotene, selenium, vitamin C and vitamin E in the prevention of coronary heart disease and stroke yielding conflicting results (positive, neutral and negative). In many of these clinical trials there are enormous clinical design problems, methodologic flaws, varied patient population, variable dose and type of vitamin use, improper selection of vitamin used and many other issues that make the studies difficult to interpret. It is beyond the scope of this paper to review these trials. The reader is referred to the vast literature on this subject.

Impact of Nonadherence to Antihypertensive Therapy

The benefits of antihypertensive therapy in reducing cardiovascular complications have been impressive. Several clinical trials in hypertension have shown that reduction of blood pressure is associated with significant decreases in the incidence of stroke, ischemic heart disease, congestive heart failure, and renal failure, irrespective of age, gender, race or ethnicity, type of antihypertensive used, or severity of hypertension.1 Nevertheless, control of hypertension remains unsatisfactory in the United States and throughout the world. Recent data from the National Health and Nutrition Examination Survey indicate that approximately 40% of hypertensive individuals are untreated, and 65% do not have their hypertension controlled to a blood pressure level of <140/90 mm Hg.2 Although control rates have improved in the past several years, the total number of patients with uncontrolled hypertension has actually increased because of the rise in hypertension prevalence during this period (Figure).3 Figure. Changes in the prevalence and control of hypertension in the United States (1988–2004). The total number of persons with uncontrolled hypertension has increased from 37 million to 42 million during the past 2 decades, even though the rate of control has increased from 27% to 35% during the same period. Data are from Cutler et al2 and Chobanian.3 Reprinted from Chobanian.3 Article see p 1598 The capability currently exists to lower blood pressure to goal levels in most hypertensive individuals. As with the treatment of other chronic illnesses in which long-term treatment is required, adherence to prescribed medications for hypertension can be a problem. Studies have shown that ≈50% of individuals discontinue antihypertensive medications within 6 to 12 months of their initiation.4 It has been assumed that inadequate adherence to antihypertensive medications and lack of persistence of therapy contribute to the development of cardiovascular complications, although little information has been available …

Beta-blockers for hypertension: Are they going out of style?

Although beta-blockers lower blood pressure in most patients, the outcomes of clinical hypertension trials of these drugs have been disappointing, and the value of beta-blockers in treating hypertensive patients who do not have compelling indications for them has been questioned. Until these drugs are proved beneficial, they should be used as antihypertensive therapy only in patients with compelling cardiac indications for them or as add-on agents in those with uncontrolled or resistant hypertension.

Large and Small Artery Cross-Talk and Recent Morbidity-Mortality Trials in Hypertension

The results of recent large clinical trials in hypertension invite re-evaluation of the mechanisms of action of antihypertensive drugs on large and small arteries in the context of their effects on cardiovascular outcomes. By increasing our understanding of the relationship between large and small artery damage, target organ damage, and clinical end points, the trials provide us with new insights into the management of hypertension. This short review aims at analyzing the following: (1) whether β-blockers may exert deleterious effects on cardiovascular CV prevention through the reduction in heart rate (HR) or the lack of arterial remodeling; (2) whether long-term arterial remodeling can explain the “legacy” effect of multifactorial treatment in patients with hypertension and type 2 diabetes mellitus (T2D); and (3) to which level diastolic BP (DBP) can be safely lowered in elderly patients with isolated systolic hypertension (ISH). Because these issues have the concept of large/small artery cross-talk in common, we analyzed it first. The damaging effect of local pulse pressure (PP) has been well demonstrated on large arteries and, to a lesser extent, on small arteries. Elevated PP can stimulate hypertrophy, remodeling (increased media:lumen ratio), or rarefaction in the microcirculation, leading to increased resistance to mean flow. Recent studies showed a close relationship between microvascular damage in the heart, brain, retina, and kidney and either PP or arterial stiffness. Indeed, significant relationships have been demonstrated between brachial PP and glomerular filtration rate,1,2 microalbuminuria,2 or white matter lesions3; between arterial stiffness and glomerular filtration rate,4,5 urinary albumin,5 retinal arteriolar narrowing,6,7 white matter lesions,3 or cognitive function8; and between carotid stiffness and glomerular filtration rate.4,5 Although not all of these relationships are independent of confounding factors,3 there is a large amount of evidence for linking the pulsatility …